1. Field of the Invention
The present invention relates to a method and an apparatus for manufacturing emulsions for use in food, drugs, cosmetics or the like, emulsions for DDSs (Drug Delivery Systems), and microspheres (fine particles) which are solid fine particles or liquid fine particles used as a microcapsule, an ion exchange resin, a chromatography carrier or the like.
2. Description of the Relevant Art
Techniques in which a biphasic system, for which a separated state is thermodynamically stable, is formed, such as that composed of a water phase and an organic phase which are emulsified to obtain a semi-stable emulsion, are conventionally known.
As general emulsification methods, there have been described in xe2x80x9cScience of Emulsionsxe2x80x9d (Asakura-shoten, 1971), the methods of using a mixer, a colloid mill, a homogenizer, etc., and the method of dispersion with sound waves, which are all well known.
The general methods mentioned above have a disadvantage in that the diameters of dispersed phase particles in a continuous phase are distributed over a wide range.
Therefore, a method of using filtration by means of a membrane comprising polycarbonate (Biochemica et Biophysica Acta, 557 (1979), North Holland Biochemical Press); a method using repeated filtrations through a PTFE (polytetrafluoroethylene) membrane (Proceedings of the 26th Autumn Meeting of the Society of Chemical Engineers, Japan, 1993); and a method of manufacturing homogenous emulsions by transferring a dispersed phase into a continuous phase through a porous glass membrane having uniform pores (Japanese Patent Application Laid-Open No. 2-95433) have been proposed. In addition, as a method of manufacturing emulsions using a nozzle or a porous plate, a laminar-flow dripping method (KAGAKU KOOGAKU Vol. 21, No. 4, 1957) is also known.
The method using filtration through a membrane comprising polycarbonate and the method using repeated filtrations through a PTFE membrane theoretically cannot manufacture emulsions comprising particles larger than the membrane pores and cannot separate particles smaller than the membrane pores. These methods are therefore especially unsuitable for producing emulsions comprising large particles.
In the method using a porous glass membrane having uniform pores, when the average diameter of the membrane pores is small, particle diameters are distributed in a narrow range and thus homogenous emulsions can be obtained. When the average diameter of the membrane pores is increased, however, particle diameters become distributed over a wide range so that homogenous emulsions cannot be obtained.
In addition, in the laminar-flow dripping method, particle sizes become 1,000 xcexcm or more and are distributed over a wide range so that homogenous emulsions cannot be obtained.
Therefore, the inventors of the present invention formerly proposed an apparatus which can continuously produce homogenous emulsions in International Publication No. WO97/30783. The structure of this apparatus is shown in FIGS. 8 and 9. FIG. 8 is a vertical sectional view of this apparatus. FIG. 9 shows a perspective exploded view wherein a base and a plate are shown taken apart. In this apparatus for producing emulsions, a supply port 102 for a continuous phase, a supply port 103 for a dispersed phase, and a withdrawal port 104 for emulsions are formed in a body 101 supported by a case 100. A bulkhead member 106 provided between the body 101 and a base 105 separates the supply port 103 for a dispersed phase from the withdrawal port 104 for emulsions. In addition, an opening 107 for a dispersed phase is formed in the center part of the base 105 and a gap is formed between the base 105 and a plate 108 placed opposite the base 105. The dispersed phase and the continuous phase are separated in a boundary section 109 formed in the base 105 and the dispersed phase and the continuous phase are mixed in a microchannels 110 formed in the boundary section 109.
The dispersed phase supplied to the inside of the bulkhead member 106 through the supply port 103 enters a gap between the plate 108 and the base 105 through the opening 107. The dispersed phase then enters the continuous phase through the microchannel 110, and thereby emulsions are formed.
As an art related to producing microspheres (fine particles) other than in emulsions, there is known a spray drying method. Spray drying method may be of three types, i.e., a centrifugal nozzle method, a pressure nozzle method and a two-fluid nozzle method. However, in each method, a turbulent flow is formed by rotating a nozzle at high speed or making a liquid flow at high speed, and the liquid is caused to form microspheres (fine particles) through a shear stress caused by the turbulent flow.
As an apparatus for manufacturing microspheres, there is also known a granulation apparatus. Granulation apparatuses of many types are known, for example: a pumping type, a centrifugal flow type, a fluidized bed type, an air current type, a stirring type or the like. However, in methods employing each of these types of granulation apparatus, microspheres (liquid drops) are formed through a shear stress caused by a turbulent flow.
In the conventional apparatus for producing emulsions, the spray dryer or the various granulation apparatuses as mentioned above, a penetrating hole of a porous membrane or a nozzle from which microspheres are pumped has a circular shape or a nearly circular shape with respect to the opening shape.
In the case where the opening shape of the portion from which the dispersed phase is pumped into the continuous phase is circular or nearly circular, since the force of a vertical direction uniformly acts on the boundary surface of the dispersed phase which is pumped from the opening, the dispersed phase is difficult to separate from the opening. Therefore, in the conventional arts, as mentioned above, a turbulent flow is formed, the dispersed phase is forced to separate from the opening through a shear stress caused by the turbulent flow, and thereby fine particles are produced.
However, in the case where microspheres (fine particles) are formed through a shear stress caused by the turbulent flow, since the dispersed phase is difficult to separate from the opening as liquid drops as mentioned above, the problem arises wherein the particle diameters of the manufactured microspheres are not uniform.
In the known apparatus in relation to, as well as particle diameter, there is another problem that relates to production efficiency. For example, in the apparatus for producing emulsions shown in FIGS. 8 and 9, it is necessary to linearly form the microchannels on the periphery of the opening which is provided in the center part of the base. The number of microchannels per a base is at most 5000 in a case of small microchannels. The number is further decreased as the size of the microchannels is increased. Therefore, it is not easy to disperse homogenous particles of the dispersed phase into the continuous phase at high efficiency and as a result there is room for improvement with respect to the production cost.
To solve the above-mentioned problems, according to the present invention, there is provided a method for manufacturing microspheres comprising the steps of separating a dispersed phase and a continuous phase by a bulkhead in which a penetrating hole is formed, applying higher pressure to the dispersed phase than the continuous phase, and thereby pumping the dispersed phase into the continuous phase, wherein a non-uniform shear stress is made to act toward the boundary surface of the dispersed phase which is pumped into the continuous phase through the penetrating hole, so that microspheres are formed.
When the non-uniform shear stress acts toward the boundary surface of the dispersed phase which is pumped into the continuous phase through the penetrating hole, the dispersed phase is easy to separate and form into microspheres, so that microspheres having a uniform particle diameter can be manufactured.
This can be achieved by making the cross-sectional shape of the penetrating hole a slot shape or the like which is not a perfect square or circle in shape. By doing so, when the dispersed phase is pumped from the penetrating hole, the force, which is perpendicular to the boundary surface and acts in the direction from the outside to the inside, has a distribution in magnitude, so that the boundary surface between the continuous phase and the dispersed phase is unstable, the shear to the boundary surface is promoted, and thereby fine and homogenous microspheres can be produced.
In a case directed to emulsions as microspheres, liquid is used as a dispersed phase and a continuous phase. In a case directed to spray drying, liquid is used as a dispersed phase and air is used as a continuous phase.
Further, the amount of microspheres produced can be controlled by the supply pressure driving the dispersed phase. The supply pressure driving the dispersed phase at which the amount of microspheres produced is maximized in the range of stably producing microspheres is detected, and the operation is conducted at such pressure.
In order to stably produce microspheres, it is required to move and supply the continuous phase existing around the boundary surface to the boundary surface at the time of shearing the boundary surface. Therefore, it is necessary that the continuous phase exist around the boundary surface at a certain amount. Also, the continuous phase needs to be supplied so as to withdraw produced microspheres. The ratio of a dispersed phase in emulsions can be optionally determined by varying the flow velocity of the continuous phase. Therefore, the optimum flow velocity of the continuous phase which satisfies the above-mentioned conditions is detected, and the operation is conducted at such flow velocity.
By flowing the continuous phase at a predetermined velocity, not only the continuous phase can be supplied to the boundary surface, but also microspheres can be promoted to separate from the exit by supplying the continuous phase with mechanical force, such as ultrasonic or the like, which is applied to the continuous phase. Such external force has an effect not on shearing of liquid drops but of promoting separation after production (shearing).
As an example of the present invention can be listed an apparatus for implementing the above-mentioned method for manufacturing microspheres. In this example, a first plate, an intermediate plate and a second plate are provided apart from each other in a case. A first flow path, from which liquid cannot escape and through which a dispersed phase flows, is provided between the first plate and the intermediate plate. A second flow path, from which liquid cannot escape and through which a continuous phase and a phase containing microspheres flow, is provided between the intermediate plate and the second plate. A number of penetrating holes which connect the first flow path and the second flow path are formed in the intermediate plate. The penetrating holes have a non-circular shape which results in non-uniform shear stress acting toward the boundary surface of the dispersed phase which is pumped therethrough into the continuous phase.
With this structure, it is possible to greatly increase the number of the penetrating holes per an intermediate plate (for example, 1000/cm2 or more), and thereby mass-production of microspheres can be achieved.
A number of units each of which comprises the first plate, the intermediate plate and the second plate may be combined in a vertically extending array, and thereby high productivity can be achieved.
The opening shape of the penetrating holes formed in the intermediate plate may be a slot shape or a shape in which slots are combined. However, it is not limited to these shapes.
As a method for forming the penetrating hole in the intermediate plate, it is preferable to use an etching treatment, irradiation of electron rays, a precision processing technique such as a CVD method or the like, or a high-density plasma etching treatment which is one among dry etching treatments.
Further, by making at least one part of the first plate or the second plate transparent, it is possible to monitor the condition of producing microspheres from outside the apparatus with a CCD camera or the like.